EP1844012A2 - Novel process for the preparation of substituted indoles - Google Patents

Novel process for the preparation of substituted indoles

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Publication number
EP1844012A2
EP1844012A2 EP06700281A EP06700281A EP1844012A2 EP 1844012 A2 EP1844012 A2 EP 1844012A2 EP 06700281 A EP06700281 A EP 06700281A EP 06700281 A EP06700281 A EP 06700281A EP 1844012 A2 EP1844012 A2 EP 1844012A2
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Prior art keywords
formula
compound
process according
methyl
vii
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German (de)
French (fr)
Inventor
Philip AstraZeneca R & D Charnwood KEEGAN
Eric AstraZeneca R & D Charnwood MERIFIELD
Duncan AstraZeneca R & D Charnwood GILL
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AstraZeneca AB
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AstraZeneca AB
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring

Definitions

  • the present invention relates to a novel process for the preparation of substituted indoles which are useful as therapeutic agents.
  • WO 04/106302 discloses a series of substituted indoles useful for the treatment of respiratory diseases.
  • the invention therefore provides a process for the preparation of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof:
  • R is an ester forming group, and optionally thereafter forming a pharmaceutically acceptable salt or solvate.
  • the reaction can be carried out in the presence of a base followed by treatment with acid and a ketone or ester containing solvent or mixtures of said solvents or mixtures comprising said solvents.
  • the compounds of formula (II) are treated with a base such as an alkali metal hydroxide in a suitable solvent such as an organic alcohol, preferably at elevated temperature.
  • the reaction mixture is then treated with acid at elevated temperature in the presence of ketone or ester-containing solvents to give the compound of formula (I).
  • the use of ketone and ester-containing solvents has surprisingly been found to promote crystal growth.
  • R is hydrogen or is as defined in formula (II) by hydrogenation followed by treatment of the resulting amine with an acetylating agent such as acetyl chloride.
  • R is an ester forming group as defined in formula (II).
  • the hydrogenation can be carried out using standard conditions such as using a platinum catalyst under a hydrogen atmosphere at elevated pressure, e.g. a pressure of about 4 bar. This reduction can also be achieved with sodium dithionite.
  • the resulting amine which is optionally isolated, for example by crystallisation from ethyl acetate/iso-hexane, is treated with acetyl chloride in a solvent such as ethyl acetate at ambient or elevated temperature, preferably at about 4O 0 C.
  • R is as defined in formula (II) and X is halogen.
  • R is ethyl and X is bromo such that the compound (V) is ethylbromoacetate.
  • the reaction is carried out in the presence of a base such as potassium carbonate in water/acetonitrile.
  • R 1 is chloro or a group that be converted to chloro such as amino or hydrogen.
  • R 1 is chloro.
  • the reaction of compounds (VI) and (VII) can be carried out using a suitable base such as sodium methoxide in methanol at elevated temperature, or a reagent such as trichloroisocyanuric acid in a solvent such as ethyl acetate or dichloromethane.
  • R is hydrogen or is as defined in formula (II) by hydrogenation and subsequent reaction of the resulting amine using analogous conditions to those described above for the hydrogenation of compound (V).
  • R is as defined in formula (II), more preferably R is ethyl.
  • Compound (IX) can be prepared from a compound of formula (VI) by reaction with a compound such as ethylbromoacetate using analogous conditions to those described above for the reaction of compound (IV).
  • compounds of formula (IH) can be prepared from compounds of formula (IX) as defined above by reacting with a compound of formula (VII) as defined above using analogous conditions to those described above for the reaction of compounds (VI) and (VII) using TCCA.
  • Trichloroisocyanuric acid (450 mg, 1.9 mmol) was added to a solution of bis(p- chlorodiphenyl)disulphide (1.63 g, 5.7 mmol) in ethyl acetate (10 ml) at ambient temperature, resulting in the formation of an orange suspension.
  • a suspension of 2-methyl-4-nitro-lH-indole (2.0 g, 11.3 mmol) in ethyl acetate 25 (10 ml) was added followed by an ethyl acetate rinse (4 ml), using water bath cooling to control the mild exotherm. Stirring was continued at ambient temperature for 40 minutes.
  • Aqueous sodium bicarbonate (5%, 20 ml) and water (20 ml) were added and the resulting suspension stirred at ambient temperature for 45 minutes.
  • the solid was collected by filtration, washed with water (2 x 10 ml), followed by ethyl acetate (2 x 10 ml) then dried in a vacuum oven at 45 0 C to provide 3-(4-chlorophenylsulfanyl)-2-methyl-4-nitro-lH-indole, 2.9 g (81%) as a yellow / brown solid.
  • Aqueous sodium hydroxide (1 M, 11.7 kg) was added to a solution of [4-acetylamino- 3 -(4-chlorophenylsulfanyl)-2-methyl-lH-indol-l-yl] acetic acid, ethyl ester (2.20 kg, 5.28 mol) in 1-propanol (8.2 kg) and the mixture heated to 68 0 C. After cooling to 40 0 C, the solution was filtered, the filter rinsed with water (1 kg) then methyl zsobutyl ketone (17.8 kg) was added to the filtrate, which was re-heated to 80 0 C.
  • Aqueous hydrochloric acid (1 M, 12.2 kg) was added over a period of 90 minutes then the mixture cooled to 19 0 C.
  • the crystalline solid was collected by filtration, washed with water (2 x 4 kg), ethyl acetate (6 kg) then dried in a vacuum oven at 40 0 C to provide [4-acetylamino-3-(4-chlorophenylsulfanyi)-2- methyl-lH-indol-l-yl]acetic acid as white crystals, 1.87 kg (91%).
  • Trichloroisocyanuric acid (0.15 g, 0.65 mmol) was added to a solution of bis(p- chlorophenyl)disulphide (0.55 g, 1.9 mmol) in ethyl acetate (5.25 ml) at ambient temperature resulting in formation of a yellow suspension.
  • Trichloroisocyanuric acid (0.13 g, 0.56 mmol) was added to a solution of bis(p- chlorophenyl)disulphide (0.47 g, 1.6 mmol) in ethyl acetate (5 ml) at ambient temperature resulting in formation of a yellow suspension.
  • ethyl acetate 5 ml
  • a slurry of (4-acetylamino-2 -methyl- lH-indol-l-yl)acetic acid (0.80 g, 3.2 mmol) in ethyl acetate (10 ml) was added followed by an ethyl acetate rinse (5 ml), using water bath cooling to control the mild exotherm.
  • Aqueous sodium hydroxide (1 M, 25 ml) was added to a solution of (4-nitro-2-methyl- l/J-indol-l-yl)acetic acid, ethyl ester (5.0 g, 18.9 mmol) in ethanol (25 ml) and the mixture warmed to 40 0 C. After stirring for 70 mins at this temperature, the mixture was allowed to cool back to ambient temperature and aqueous hydrochloric acid (1 M, 27.5 ml) added causing precipitation of a solid.
  • Trichloroisocyanuric acid (0.51 g, 2.2 mmol) was added to a solution of bis(p- chlorophenyl)disulphide (1.84 g, 6.4 mmol) in ethyl acetate (15 ml) at ambient temperature resulting in formation of a yellow suspension.
  • ethyl acetate 15 ml
  • a slurry of (4-nitro-2-methyl-lH-indol-l-yl)-acetic acid (3.0 g, 12.8 mmol) in ethyl acetate (30 ml) was added followed by an ethyl acetate rinse (6 ml). Stirring was continued for 40 minutes at ambient temperature.
  • the product can be converted to a compound of formula (I) by reduction of the nitro group followed by amide formation using a process analogous to that given above for [4- Acetylamino-3-(4-chlorophenylsulfanyl)-2-methyl-lH ; -indol-l-yl] acetic acid, ethyl ester: method A

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Indole Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

The invention relates to a novel process for the preparation of substituted indoles which are useful as therapeutic agents.

Description

NOVEL PROCESS
The present invention relates to a novel process for the preparation of substituted indoles which are useful as therapeutic agents. WO 04/106302 discloses a series of substituted indoles useful for the treatment of respiratory diseases.
New processes have now been developed for certain compounds which are more > efficient than those disclosed in the art.
In a first aspect the invention therefore provides a process for the preparation of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof:
(I) which comprises de-esterification of a compound of formula (II):
(H) in which R is an ester forming group, and optionally thereafter forming a pharmaceutically acceptable salt or solvate. The reaction can be carried out in the presence of a base followed by treatment with acid and a ketone or ester containing solvent or mixtures of said solvents or mixtures comprising said solvents. The compounds of formula (II) are treated with a base such as an alkali metal hydroxide in a suitable solvent such as an organic alcohol, preferably at elevated temperature. The reaction mixture is then treated with acid at elevated temperature in the presence of ketone or ester-containing solvents to give the compound of formula (I). The use of ketone and ester-containing solvents has surprisingly been found to promote crystal growth. Suitable solvents include ethyl acetate, n-propylacetate and MIBK and mixtures thereof. Preferably MIBK is used. Preferably the compound of formula (II) is treated with aqueous sodium hydroxide in n-propanol at elevated temperature, for example at about 68°C. Preferably the group R is phenyl, benzyl or a C1-6alkyl group such as methyl or ethyl, preferably R is C1-6alkyl, more preferably ethyl.
Compound of formula (II) are prepared by reaction of compounds of formula (III):
(III) in which R is hydrogen or is as defined in formula (II) by hydrogenation followed by treatment of the resulting amine with an acetylating agent such as acetyl chloride. Preferably R is an ester forming group as defined in formula (II). The hydrogenation can be carried out using standard conditions such as using a platinum catalyst under a hydrogen atmosphere at elevated pressure, e.g. a pressure of about 4 bar. This reduction can also be achieved with sodium dithionite. The resulting amine, which is optionally isolated, for example by crystallisation from ethyl acetate/iso-hexane, is treated with acetyl chloride in a solvent such as ethyl acetate at ambient or elevated temperature, preferably at about 4O0C.
Compounds of formula (III) can be prepared by reacting compounds of formula (TV):
(IV) with compounds of formula (V):
XCH2CO2R (V) in which R is as defined in formula (II) and X is halogen. Preferably R is ethyl and X is bromo such that the compound (V) is ethylbromoacetate. The reaction is carried out in the presence of a base such as potassium carbonate in water/acetonitrile.
Compounds of formula (IV) can be prepared by reacting compounds of formula (VI):
(VI) with compounds of formula (VII):
(VII) . in which R1 is chloro or a group that be converted to chloro such as amino or hydrogen. Preferably R1 is chloro. The reaction of compounds (VI) and (VII) can be carried out using a suitable base such as sodium methoxide in methanol at elevated temperature, or a reagent such as trichloroisocyanuric acid in a solvent such as ethyl acetate or dichloromethane.
In an alternative embodiment of the invention compounds of formula (II) can be prepared from compounds of formula (VIII):
(VIII) in which R is hydrogen or is as defined in formula (II) by reacting with a compound of formula (VII). The reaction can be carried out using trichloroisocyanuric acid as described above. This reaction is advantageous where R is hydrogen as it can be used for the direct preparation of compounds of formula (I).
Compounds of formula (VIII) can be prepared from compounds of formula (IX):
(IX) in which R is hydrogen or is as defined in formula (II) by hydrogenation and subsequent reaction of the resulting amine using analogous conditions to those described above for the hydrogenation of compound (V). Preferably R is as defined in formula (II), more preferably R is ethyl. Compound (IX) can be prepared from a compound of formula (VI) by reaction with a compound such as ethylbromoacetate using analogous conditions to those described above for the reaction of compound (IV).
In a still further embodiment of the invention compounds of formula (IH) can be prepared from compounds of formula (IX) as defined above by reacting with a compound of formula (VII) as defined above using analogous conditions to those described above for the reaction of compounds (VI) and (VII) using TCCA.
All novel intermediates disclosed herein form a further aspect of the invention, hi a further aspect the invention therefore provides a compound of formula (VIII) and (IX).
The following examples illustrate the invention.
Example 1 3-(4-ChlorophenylsuIfanyl)-2-methyl-4-nitro-lH-indole
Method A
Sodium methoxide in methanol (4.1 kg, 25% w/w, 19 mol) was added to a stirred suspension of 2-methyl-4-nitro-17i-indole (1.52 kg, 8.6 mol) and bis(p- io chlorophenyl)disulphide (2.48 kg, 8.6 mol) in methanol (6.47 kg) followed by a methanol line rinse (0.67 kg). The mixture was then heated at 60 - 65 0C for 3.5 hours. Water (6.1 kg) was added to the reaction mixture, which was then cooled to 20 0C and stirred at this temperature for 7 minutes. The solid was collected by filtration, washed with water (2 x 4 kg) followed by ethyl acetate (2 x 4 kg) then dried in a vacuum oven at 40 0C. 3-(4-Chlorophenylsulfanyl)-2-
I5 methyl-4-nitro-lH'-indole was obtained as a bright yellow solid, 2.57 kg (93% yield).
1H NMR (400 MHz, D6-DMSO) δ 7.77 (d, J= 7.9 Hz, IH), 7.63 (d, J= 7.6 Hz, IH), 7.27 (m, 3H), 6.92 (d, J= 8.8 Hz, 2H), 2.48 (s, 3H). LC-MS (ES+): 319 (100%, MH+).
20 Method B
Trichloroisocyanuric acid (450 mg, 1.9 mmol) was added to a solution of bis(p- chlorodiphenyl)disulphide (1.63 g, 5.7 mmol) in ethyl acetate (10 ml) at ambient temperature, resulting in the formation of an orange suspension. After stirring at ambient temperature for 30 minutes, a suspension of 2-methyl-4-nitro-lH-indole (2.0 g, 11.3 mmol) in ethyl acetate 25 (10 ml) was added followed by an ethyl acetate rinse (4 ml), using water bath cooling to control the mild exotherm. Stirring was continued at ambient temperature for 40 minutes. Aqueous sodium bicarbonate (5%, 20 ml) and water (20 ml) were added and the resulting suspension stirred at ambient temperature for 45 minutes. The solid was collected by filtration, washed with water (2 x 10 ml), followed by ethyl acetate (2 x 10 ml) then dried in a vacuum oven at 45 0C to provide 3-(4-chlorophenylsulfanyl)-2-methyl-4-nitro-lH-indole, 2.9 g (81%) as a yellow / brown solid.
f3-(4-ChlorophenvIsuIfanyl)-2-methyl-4-nitro-ljΗ-indoI-l-yl1 acetic acid, ethyl ester: method A
3-(4-Chlorophenylsulfanyl)-2-methyl-4-nitro-l/f-indole (3.76 kg, 11.8 mol) and potassium carbonate (1.80 kg, 13.0 mol) were suspended in acetonitrile (32.7 kg). Water (0.53 kg) and a solution of ethyl bromoacetate (2.17 kg, 13.0 mol) in acetonitrile (5.75 kg) were added followed by an acetonitrile line rinse (2.97 kg). The mixture was heated at 50 0C for 6 hours then allowed to cool to 20 0C and held at this temperature overnight. Water (35.4 kg) was added to the reaction mixture and stirring continued for 30 minutes at 15 0C. The solid product was collected by filtration, washed with acetonitrile (2.95 kg) then dried in a vacuum oven at 40 0C to afford [3-(4-chlorophenylsulfanyl)-2-methyl-4-nitro-lH-indol-l- yl]acetic acid, ethyl ester as a bright yellow solid, 4.33 kg (91%).
1H NMR (300 MHz, D6-DMSO) δ 7.97 (dd, J- 8.3, 0.8 Hz, IH), 7.65 (dd, J= 7.9, 0.8 Hz, IH), 7.34 (t, J= 8.1 Hz, IH), 7.26 (m, 2H), 6.92 (m, 2H), 5.40 (s, 2H), 4.19 (q, J= 7.0 Hz, 2H), 2.45 (s, 3H), 1.22 (t, J= 7.1 Hz, 3H). LC-MS (ES+): 405 (100%, MH+), 407 (MH+). |4-Acetylamino-3-(4-chlorophenylsulfanyl)-2-methyl-lJ3r-indoI-l-vn acetic acid, ethyl ester: method A
A solution of [3-(4-chlorophenylsulfanyl)-2-methyl-4-nitro-lHr-indol-l-yl]acetic acid, ethyl ester (1.99 kg, 4.92 mol) in ethyl acetate (24.2 kg) was hydrogenated in the presence of a 1% Pt / C catalyst paste (1.39 kg 44% w/w) under 4 bar A hydrogen pressure. After 2 hours hydrogen uptake had ceased so the reaction mixture was inerted then filtered through Celite o (2.60 kg). The solids were washed with ethyl acetate (3 x 8 kg) and the combined filtrates distilled until a volume of 26 L remained to leave a solution of [4-amino-3-(4- chlorophenylsulfanyl)-2-methylindol-l-yl] acetic acid, ethyl ester in ethyl acetate. This solution was cooled to 4 0C then triethylamine (0.50 kg, 4.94 mol) added, followed by an ethyl acetate line wash (0.82 kg). A solution of acetyl chloride (0.39 kg, 4.97 mol) in ethyl s acetate (3 kg) was added followed by an ethyl acetate line wash (0.76 kg). The reaction mixture was heated at 40 0C for 17 hours then water (16.9 kg) added. The reaction mixture was distilled down until 24.6 kg of distillate had been removed then cooled to 200C. The solid product was collected by filtration, washed with water (1.9 kg) followed by acetonitrile (1.6 kg) then dried in a vacuum oven at 400C to afford [4-acetylamino-3-(4- 0 chlorophenylsulfanyl)-2-methyl-lH-indol-l-yl] acetic acid, ethyl ester, 1.69 kg (82%) as an off white solid.
1H NMR (300 MHz, DMSO) δ 9.51 (s, IH), 7.46 (d, J= 7.5 Hz, IH), 7.36 - 7.25 (m, 3H), 7.11 (t, J= 8.0 Hz, IH), 6.97 (d, J= 8.7 Hz, 2H), 5.24 (s, 2H), 4.18 (q, J= 7.1 Hz, 2H), 2.39 (s, 3H)5 1.86 (s, 3H), 1.21 (t, J= 7.1 Hz, 3H). s LC-MS (ES+): 417 (100%, MH+), 419 (MH+). f4-AcetvIamino-3-(4-chlorophenvlsulfanvlV2-methvl-lH-indol-l-vllacetic Acid
Aqueous sodium hydroxide (1 M, 11.7 kg) was added to a solution of [4-acetylamino- 3 -(4-chlorophenylsulfanyl)-2-methyl-lH-indol-l-yl] acetic acid, ethyl ester (2.20 kg, 5.28 mol) in 1-propanol (8.2 kg) and the mixture heated to 68 0C. After cooling to 40 0C, the solution was filtered, the filter rinsed with water (1 kg) then methyl zsobutyl ketone (17.8 kg) was added to the filtrate, which was re-heated to 80 0C. Aqueous hydrochloric acid (1 M, 12.2 kg) was added over a period of 90 minutes then the mixture cooled to 19 0C. The crystalline solid was collected by filtration, washed with water (2 x 4 kg), ethyl acetate (6 kg) then dried in a vacuum oven at 40 0C to provide [4-acetylamino-3-(4-chlorophenylsulfanyi)-2- methyl-lH-indol-l-yl]acetic acid as white crystals, 1.87 kg (91%).
1H NMR (400 MHz, D6-DMSO) δ 9.51 (s, IH), 7.47 (d, J= 7.6 Hz, IH), 7.38 - 7.24 (m, 3H), 7.11 (t, J= 8.1 Hz, IH), 6.98 (d, J= 8.5 Hz, 2H), 5.12 (s, 2H), 2.40 (s, 3H), 1.86 (s, 3H).
LC-MS (ES+): 389 (100%, MH+), 391 (MH+).
(4-Nitro-2-methyl-lH-indol-l-yl)-acetic acid, ethyl ester
Water (4.5 ml), potassium carbonate (25.9 g, 187 mmol) and ethyl bromoacetate (20.8 ml, 188 mmol) were added sequentially to a suspension of 2-methyl-4-nitro-lH-indole (30 g, 170 mmol) in acetonitrile (225 ml) and the mixture heated at 60 0C for 16 hours. After allowing to cool to ambient temperature, water (225 ml) was added and the resulting mixture was broken up and then filtered. The solid was washed with water (2 x 75 ml), followed by IMS (2 x 75 ml) then dried in a vacuum oven to give (4-nitro-2-methyl-lH-indol-l-yl)-acetic acid, ethyl ester, 32.15 g (72%).
1H-NMR (300 MHz, D6-DMSO) δ 8.04 (d, J= 8.1 Hz, IH), 7.93 (d, J= 8.1 Hz, IH), 5 7.27 (t, J= 8.1 Hz, IH), 6.93 (s, IH), 5.25 (s, 2H), 4.17 (q, J= 7.1 Hz, 2H), 2.44 (s, 3H), 1.21 (t, J = 7. I Hz, 3H)
LC-MS (ES+): 263 (100%, MH+)
[3-(4-ChlorophenylsuIfanyl)-2-methvI-4-nitro-l£f-indol-l-vIl acetic acid, ethyl ester: it) method B
Trichloroisocyanuric acid (0.30 g, 1.3 mmol) was added to a solution of bis(p- chlorophenyl)disulphide (1.08 g, 3.8 mmol) in ethyl acetate (10 ml) at ambient temperature is resulting in formation of a yellow suspension. After stirring for 30 minutes at this temperature, a slurry of (4-nitro-2-methyl-lH-indol-l-yl)-acetic acid, ethyl ester (2.0 g, 7.6 mmol) in ethyl acetate (10 ml) was added followed by an ethyl acetate rinse (4 ml), using water bath cooling to control the mild exotherm. Stirring was continued for 35 minutes at ambient temperature. Aqueous sodium bicarbonate (5%, 20 ml) was added followed by water
20 (20 ml). After stirring for 45 minutes, ethyl acetate was removed by evaporation, the solid product collected by filtration, washed with water (2 x 10 ml), followed by 50% v/v aqueous acetonitrile (2 x 10 ml) then dried overnight in a vacuum oven at 45 0C to provide [3-(4- chlorophenylsulfanyl)-2-methyl-4-nitro-lH-indol-l-yl] acetic acid, ethyl ester as a bright yellow solid, 2.95 g (96%).
25 (4-Amino-2-methyl-lHr-indol-l-yl)-acetic acid, ethyl ester
5 A solution of (4-nitro-2-methyl-lJi-indol-l-yl)-acetic acid, ethyl ester (5.0 g, 19 mmol) in ethyl acetate (75 ml) was hydrogenated under 3 bar hydrogen pressure in the presence of a wet 1% Pt / C catalyst paste (38 w/w, 0.7 g) until hydrogen uptake ceased (3 hours). The reaction mixture was filtered through kieselguhr and the solids washed with ethyl acetate (75 ml). The filtrate and wash were combined with solutions obtained from 2 o previous experiments which had been carried out in a similar manner, each on a 2 g scale, and evaporated to dryness to provide (4-amino-2-methyl-lH-indol-l-yl)-acetic acid, ethyl ester, 8.59 g, >100% as a brown oil which solidified on standing.
1H NMR (300 MHz, D6-DMSO) δ 6.73 (t, J= 7.9 Hz, IH), 6.49 (d, J= 8.1 Hz, IH), 6.28 (s, IH), 6.15 (d, J= 7.5 Hz, IH), 5.05 (br s, 2H), 4.89 (s, 2H), 4.13 (q, J= 7.1 Hz, 2H), s 2.27 (s, 3H), 1.20 (t, J= 7.1 Hz, 3H). LC-MS (ES+): 233 (100%, MH+).
(4-Acetylamino-2-methyl-lH-indol-l-yl)-acetic acid ethyl ester
o The (4-amino-2-methyl-lH-indol-l-yl)-acetic acid, ethyl ester prepared above (8.59 g) was dissolved in ethyl acetate (175 ml) then triethylamine (5.2 ml, 37 mmol) added followed by acetyl chloride (2.6 ml, 37 mmol). An exotherm to 35 0C was observed and a thick suspension resulted. After stirring for 4 hours during which the mixture was allowed to cool back to ambient temperature, water (85 ml) was added and the ethyl acetate removed by evaporation under vacuum. The solid was collected by filtration, washed with water (25 ml) followed by 50% v/v aqueous acetonitrile (50 ml) then dried in a vacuum oven at 50 0C overnight to provide (4-acetylamino-2-methyl-lH-indol-l-yl)-acetic acid, ethyl ester, as an off-white solid, 7.26 g (77% from (4-nitro-2-methyl-lH-indol-l-yl)-acetic acid, ethyl ester). 1H NMR (300 MHz, D6-DMSO) δ 9.51 (s, IH), 7.55 (d, J= 7.7 Hz, IH), 7.07 (d, J= 8.1 Hz, IH), 6.96 (t, J= 7.9 Hz, IH), 6.50 (s, IH), 5.02 (s, 2H), 4.14 (q, J= 7.1 Hz, 2H), 2.33 (s, 3H)5 2.12 (s, 3H), 1.20 (t, J= 7.1 Hz, 3H). LC-MS (ES+): 275 (100%, MH+).
[4-Acetylamino-3-(4-chloro-phenvIsulfanyl)-2-methyl-lHr-indol-l-yll-acetic acid, ethyl ester: method B
Trichloroisocyanuric acid (0.15 g, 0.65 mmol) was added to a solution of bis(p- chlorophenyl)disulphide (0.55 g, 1.9 mmol) in ethyl acetate (5.25 ml) at ambient temperature resulting in formation of a yellow suspension. After stirring for 15 minutes at this temperature, a slurry of (4-acetylamino-2 -methyl- lH-indol-l-yl)-acetic acid, ethyl ester (1.05 g, 3.8 mmol) in ethyl acetate (5.25 ml) was added, followed by an ethyl acetate rinse (2 ml), using water bath cooling to control the mild exotherm. Stirring was continued for Ih 15 minutes at ambient temperature. Aqueous sodium bicarbonate (5%, 10.5 ml) was added followed by water (10.5 ml). After stirring for 35 minutes, the solid product was collected by filtration, washed with water (2 x 5 ml) then dried in a vacuum oven at 45 0C overnight to give [4-acetylamino-3-(4-chlorophenylsulfanyl)-2-methyl-lH-indol-l-yl]-acetic acid, ethyl ester as a grey solid, 1.13 g, 71%). (4-Acetylamino-2-methyl-lJH-indol-l-yI)acetic acid
(4-Acetylamino-2-methyl-lH-indol-l-yl)-acetic acid, ethyl ester (2.0 g, 7.3 mmol) was slurried in ethanol (10 ml) at ambient temperature. Aqueous sodium hydroxide (I M, 10 ml, 10 mmol) was added and the mixture heated to 50 0C. The solution obtained at was then allowed to cool back to ambient temperature and aqueous hydrochloric acid (1 M, 11 ml, 11 mmol) added. The resulting solid was collected by filtration, washed with water (2 x 10 ml) then dried in a vacuum oven at 45 0C overnight to provide (4-acetylamino-2-methyl-lH- indol-l-yl)acetic acid as an off-white solid, 1.66 g (92%).
1H NMR (300 MHz, D6-DMSO) δ 12.97 (s, IH), 9.49 (s, IH), 7.54 (d, J= 7.5 Hz, IH), 7.07 (d, J= 8.1 Hz, IH), 6.95 (t, J= 7.9 Hz, IH), 6.49 (s, IH), 4.91 (s, 2H), 2.33 (d, J= 0.8 Hz, 3H), 2.12 (s, 3H) LC-MS (ES+): 247 (100%, MH+).
f4-Acetylamino-3-(4-chlorophenylsuIfanvI)-2-methyl-lH-indol-l-yIl acetic Acid: method B
Trichloroisocyanuric acid (0.13 g, 0.56 mmol) was added to a solution of bis(p- chlorophenyl)disulphide (0.47 g, 1.6 mmol) in ethyl acetate (5 ml) at ambient temperature resulting in formation of a yellow suspension. After stirring for 15 minutes at this temperature, a slurry of (4-acetylamino-2 -methyl- lH-indol-l-yl)acetic acid (0.80 g, 3.2 mmol) in ethyl acetate (10 ml) was added followed by an ethyl acetate rinse (5 ml), using water bath cooling to control the mild exotherm. Stirring was continued for 1 h 15 minutes at ambient temperature. The solid product was collected by filtration, washed with ethanol (2 x 10 ml) then dried overnight in a vacuum oven at 45 0C to provide [4-acetylamino-3-(4- chlorophenylsulfanyl)-2-methyl-lH-indol-l-yl] acetic acid as an off-white solid, 1.22 g (97%).
Example 2 (2-Methyl-4-nitro-lH-indoI-l-yI)acetic acid
Aqueous sodium hydroxide (1 M, 25 ml) was added to a solution of (4-nitro-2-methyl- l/J-indol-l-yl)acetic acid, ethyl ester (5.0 g, 18.9 mmol) in ethanol (25 ml) and the mixture warmed to 40 0C. After stirring for 70 mins at this temperature, the mixture was allowed to cool back to ambient temperature and aqueous hydrochloric acid (1 M, 27.5 ml) added causing precipitation of a solid. This was collected by filtration, washed with water (2 x 25 ml) then dried in a vacuum oven at 50 0C overnight to leave (2-methyl-4-nitro-lH-indol-l- yl)acetic acid as a yellow solid, 4.18 g (94%). 1H-NMR (300 MHz, D6-DMSO) δ 13.2 (s, IH), 8.03 (d, J= 8.1 Hz, IH), 7.93 (d, J=
8.1 Hz, IH), 7.26 (t, J= 8.1 Hz, IH), 6.92 (s, IH), 5.13 (s, 2H), 2.45 (s, 3H) LC-MS (ES+): 235 (100%, MH+) f3-(4-ChIorophenylsulfanyl)-2-methyl-4-nitro-li?-indol-l-yll acetic acid
Trichloroisocyanuric acid (0.51 g, 2.2 mmol) was added to a solution of bis(p- chlorophenyl)disulphide (1.84 g, 6.4 mmol) in ethyl acetate (15 ml) at ambient temperature resulting in formation of a yellow suspension. After stirring for 5 minutes at this temperature, a slurry of (4-nitro-2-methyl-lH-indol-l-yl)-acetic acid (3.0 g, 12.8 mmol) in ethyl acetate (30 ml) was added followed by an ethyl acetate rinse (6 ml). Stirring was continued for 40 minutes at ambient temperature. The solid product was collected by filtration, washed with ethyl acetate (2 x 10 ml) then dried overnight in a vacuum oven at 50 0C to provide [3-(4- chlorophenylsulfanyl)-2-methyl-4-nitro-lH-indol-l-yl] acetic acid as a bright yellow solid, 2.93 g. The by-product, cyanuric acid, was not removed during the work up.
1H NMR (300 MHz, D6-DMSO) δ 13.4 (s, IH), 7.97 (dd, J= 8.3, 0.8 Hz, IH), 7.64 (dd, J= 7.7, 0.8 Hz, IH), 7.34 (t, J= 8.1 Hz, IH), 7.25 (m, 2H), 6.92 (m, 2H), 5.28 (s, 2H), 2.45 (s, 3H).
LC-MS (ES+): 377 (100%, MH+), 379 (MH+).
The product can be converted to a compound of formula (I) by reduction of the nitro group followed by amide formation using a process analogous to that given above for [4- Acetylamino-3-(4-chlorophenylsulfanyl)-2-methyl-lH;-indol-l-yl] acetic acid, ethyl ester: method A

Claims

Claims
1. A process for the preparation of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof:
(I) which comprises de-esterification of a compound of formula (II):
(H) in which R is an ester forming group, in the presence of a base followed by treatment with an acid and a ketone or ester containing solvent, and optionally thereafter forming a pharmaceutically acceptable salt or solvate.
2. A process according to claim 1 in which R is C1-6alkyl.
3. A process according to claim 1 or 2 in which R is ethyl.
4. A process according to any one of claims 1 to 3 which is carried out using an alkali metal hydroxide in an organic alcohol solvent.
5. A process according to any one of claims 1 to 4 which is carried out using aqueous sodium hydroxide in n-propanol.
6. A process according to any one of claims 1 to 5 which is carried out at a temperature 5 of about 68°C.
7. A process according to any one of claims 1 to 5 in which the acid treatment is carried out in the presence of ethyl acetate, n-propylacetate and MIBK and mixtures thereof.
Q 8. A process according to any one of claims 1 to 5 which the acid treatment is carried out in the presence of MIBK.
9. A compound of formula (I) prepared using the process according to any one of claims l to 8. s
10. A process for the preparation of a compound of formula (I) or (II) which comprises reaction of a compound of formula (VIII):
Q (VIII) in which R is hydrogen or is as defined in formula (II) by reacting with a compound of formula (VII).
5
(VII) in which R1 is chloro or a group that can be converted to chloro, and optionally thereafter forming a pharmaceutically acceptable salt or solvate.
11. A process for the preparation of a compound of formula (II) or the corresponding 5 carboxylic acid which comprises reducing a compound of formula (III):
(III) in which R is hydrogen or is as defined in formula (II) with sodium dithionite or by Q hydrogenation followed by amide formation.
12. A process for the preparation of a compound of formula (III) or the corresponding carboxylic acid which comprises reaction of a compound of formula (IX):
s
(IX) in which R is hydrogen or is as defined in formula (II) with a compound of formula
(VII): Q
(VII). in which R1 is chloro or a group that can be converted to chloro.
13. A process for the preparation of compounds of formula (IV) by reacting compounds of formula (VI):
(VI) with compounds of formula (VII):
-s-s R'
^ // Q
(VII) in which R1 is chloro or a group that can be converted to chloro.
14. A compound of formula (VIII) : s
(vπi) in which R is hydrogen, phenyl, benzyl or C1-6 alkyl.
Q 15. A compound of formula (IX) :
(IX) in which R is hydrogen, phenyl, benzyl or C1-6 alkyl.
EP06700281A 2005-01-13 2006-01-09 Novel process for the preparation of substituted indoles Withdrawn EP1844012A2 (en)

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Families Citing this family (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
TW200307542A (en) * 2002-05-30 2003-12-16 Astrazeneca Ab Novel compounds
SE0202241D0 (en) * 2002-07-17 2002-07-17 Astrazeneca Ab Novel Compounds
SE0301569D0 (en) * 2003-05-27 2003-05-27 Astrazeneca Ab Novel compounds
SE0302232D0 (en) * 2003-08-18 2003-08-18 Astrazeneca Ab Novel Compounds
SE0303180D0 (en) * 2003-11-26 2003-11-26 Astrazeneca Ab Novel compounds
GB0500604D0 (en) 2005-01-13 2005-02-16 Astrazeneca Ab Novel process
WO2007138282A2 (en) * 2006-05-26 2007-12-06 Astrazeneca Ab Bi-aryl or aryl-heteroaryl substituted indoles
MX2012000229A (en) 2009-07-06 2012-01-25 Astrazeneca Ab Intermediates and processes for the preparation of 4- (acetylamino) ) -3- [ (4-chloro-phenyl) thio] -2-methyl-1h-indole-1-acetic acid.
EA026456B1 (en) 2011-12-16 2017-04-28 Атопикс Терапьютикс Лимитед Pharmaceutical composition based on crth2 antagonist and a proton pump inhibitor for the treatment of eosinophilic esophagitis
CN103288707B (en) * 2013-05-28 2015-12-23 浙江大学 A kind of preparation method of 3-benzene sulfydryl indole derivative

Family Cites Families (38)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
BE790679A (en) 1971-11-03 1973-04-27 Ici Ltd INDOLE DERIVATIVES
JPH0615542B2 (en) 1986-07-22 1994-03-02 吉富製薬株式会社 Pyrazolopyridine compound
US5095031A (en) 1990-08-20 1992-03-10 Abbott Laboratories Indole derivatives which inhibit leukotriene biosynthesis
WO1993005020A1 (en) 1991-09-06 1993-03-18 Merck & Co., Inc. Indoles as inhibitors of hiv reverse transcriptase
FR2692574B1 (en) 1992-06-23 1995-06-23 Sanofi Elf 4-HYDROXY BENZENETHIO DERIVATIVES, THEIR PREPARATION AND THEIR USE FOR THE PREPARATION OF AMINOALKOXYBENZENESULFONYL DERIVATIVES.
AU6254294A (en) 1993-02-24 1994-09-14 Merck & Co., Inc. Inhibitors of hiv reverse transcriptase
US5486525A (en) 1993-12-16 1996-01-23 Abbott Laboratories Platelet activating factor antagonists: imidazopyridine indoles
US5567711A (en) 1995-04-19 1996-10-22 Abbott Laboratories Indole-3-carbonyl and indole-3-sulfonyl derivatives as platelet activating factor antagonists
TW472045B (en) 1996-09-25 2002-01-11 Astra Ab Protein kinase C inhibitor compounds, method for their preparation, pharmaceutical composition thereof and intermediate used for their preparation
ZA987554B (en) 1997-08-21 2000-02-21 American Home Prod Methods for the solid phase synthesis of substituted indole compounds.
PT924209E (en) 1997-12-19 2003-08-29 Lilly Co Eli IMIDAZOLINE COMPOUNDS HYPOGLYCELLANES
US6916841B2 (en) 1998-02-25 2005-07-12 Genetics Institute, Llc Inhibitors of phospholipase enzymes
AU5886500A (en) 1999-06-23 2001-01-09 Sepracor, Inc. Indolyl-benzimidazole antibacterials, and methods of use thereof
WO2001032621A1 (en) 1999-10-29 2001-05-10 Wakunaga Pharmaceutical Co., Ltd. Novel indole derivatives and drugs containing the same as the active ingredient
EA005212B1 (en) 1999-12-24 2004-12-30 Авентис Фарма Лимитед Azaindoles
WO2001092224A1 (en) 2000-05-31 2001-12-06 Astrazeneca Ab Indole derivatives with vascular damaging activity
US6878522B2 (en) 2000-07-07 2005-04-12 Baiyong Li Methods for the identification of compounds useful for the treatment of disease states mediated by prostaglandin D2
WO2003013510A1 (en) * 2001-08-07 2003-02-20 Smithkline Beecham P.L.C. 3-arylsulfonyl-7-piperazinyl- indoles, -benzofurans and -benzothiophenes with 5-ht6 receptor affinity for treating cns disorders
TWI317634B (en) 2001-12-13 2009-12-01 Nat Health Research Institutes Aroyl indoles compounds
PL373410A1 (en) 2002-02-01 2005-08-22 F.Hoffman-La Roche Ag Substituted indoles as alpha-1 agonists
SE0200356D0 (en) 2002-02-05 2002-02-05 Astrazeneca Ab Novel use
SE0200411D0 (en) 2002-02-05 2002-02-05 Astrazeneca Ab Novel use
EP1505061A4 (en) 2002-05-16 2007-08-22 Shionogi & Co Compound exhibiting pgd 2 receptor antagonism
TW200307542A (en) 2002-05-30 2003-12-16 Astrazeneca Ab Novel compounds
SE0201635D0 (en) 2002-05-30 2002-05-30 Astrazeneca Ab Novel compounds
SE0202241D0 (en) 2002-07-17 2002-07-17 Astrazeneca Ab Novel Compounds
SE0202463D0 (en) 2002-08-14 2002-08-14 Astrazeneca Ab Novel compounds
DE60334015D1 (en) * 2002-10-30 2010-10-14 Merck Frosst Canada Ltd PYRIDOPYRROLIZIN AND PYRIDOINDOLIZIN DERIVATIVES
PL377464A1 (en) * 2002-12-03 2006-02-06 F. Hoffmann-La Roche Ag Aminoalkoxyindoles as 5-ht6-receptor ligands for the treatment of cns-disorders
SE0301569D0 (en) 2003-05-27 2003-05-27 Astrazeneca Ab Novel compounds
SE0302232D0 (en) 2003-08-18 2003-08-18 Astrazeneca Ab Novel Compounds
AU2004283139A1 (en) 2003-10-14 2005-05-06 Oxagen Limited Compounds having CRTH2 antagonist activity
SE0303180D0 (en) 2003-11-26 2003-11-26 Astrazeneca Ab Novel compounds
GB0500604D0 (en) 2005-01-13 2005-02-16 Astrazeneca Ab Novel process
GB2422831A (en) 2005-02-04 2006-08-09 Oxagen Ltd Pyrrolopyridines and their use in the treatment of diseases mediated by PGD2 at the CRTH2 receptor
WO2007138282A2 (en) 2006-05-26 2007-12-06 Astrazeneca Ab Bi-aryl or aryl-heteroaryl substituted indoles
RU2008152763A (en) 2006-06-08 2010-07-20 Ньюроки А/С (Dk) APPLICATION OF CANNABINOID RECEPTOR AGONISTS AS MEDICINES HYPOTHERMIC INDUCING FOR TREATMENT OF ISCHEMIA
BRPI0713064A2 (en) 2006-06-28 2012-07-17 Sanofi Aventis cxcr2 inhibitors

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO2006075139A2 *

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